Receptors for immunoglobulin, FcRs, may influence autoimmune disease by modulating both afferent and efferent limbs of the immune response. In the afferent limb, B cell FcRs (FcgammaRII) modulate lymphocyte activation by inhibiting proliferation and antibody production in response to co- ligation of BCR and FcRII. Defects in this pathway, illustrated by the motheaten mouse, may, in part, account for the B cell defects manifested by this mutation. In the efferent limb, FcRs on effector cells, such as macrophages, neutrophils, mast cells and natural killer cells (FcgammaRI and III), engage immune complexes and cytotoxic antibodies and activate effector cells and soluble pro-inflammatory mediators. Mouse strains with specific deficiencies in each of these receptors will be used to investigate the contribution of these receptor systems to autoimmune disease. Preliminary analysis of mice deficient in FcgammaRI and III suggest a role for these receptors in the efferent limb of autoimmune disease. These mice fail to mount an inflammatory response to immune complexes in a standard model of type III inflammation, the Arthus reaction. Similarly, FcR deficient mice are protected from the pathological consequences of anti-RBC and anti-platelet antibodies. In contrast, complement C3 deficient mice have normal responses in these models of type II and III inflammation. These studies suggest that mice deficient in FcgammaRI and III may be expected to manifest less severe phenotypes in response to autoantibody triggered disease. The efferent role of FcRs in the pathophysiology of inherited murine models of autoimmunity, such as NZM and MRL/lpr will be assessed by crossing these strains with FcR deficient ones. Passive models of glomerulonephritis such as those induced by the introduction of heterologous anti-glomerular antibodies or displayed by Balb/C mice carrying a transgene expressing an IgG2b anti-DNA antibody will also be studied in FcR deficient animals. In its afferent role, lymphocytes from FcgammaRII deficient mice lack the ability to display feedback inhibition of immune complexes on B cell proliferation in vitro and may be expected to display similar defects in vivo. FcRII will be tested as a candidate gene for the recently defined NZM allele linked to chromosome 1. This potential allellism will be tested in a NZM chromosome 1 congenic crossed to an FcRII knockout. The in vivo role of FcRII in B cell regulation will be tested by challenging mice deficient in this gene with a variety of antigens, including T dependent, T independent and autoantigens. These immune responses will be compared to those displayed by autoimmune strains of mice. These studies will further explore the role of antibody receptors in autoimmune disease and may identify new targets for therapeutic intervention.